Cancer is a multistep process and occurs as a result of the loss of control of cell division, leading to initial tumour formation, which can then spread and develop a tumor in a distant organ or metastasis.
A distinguishing feature of malignant cells is their ability to invade surrounding normal tissue, metastasize through the blood and lymphatic systems and re-establish at distant secondary locations. To form metastases, individual tumour cells must break from the primary tumor mass, degrade extracellular matrix, invade the surrounding normal tissue, enter the blood or lymphatic circulation, exit the circulation at a distal tissue and establish satellite colonies within this new tissue environment. This behavior requires the cooperative function of numerous proteins. This metastatic spread of solid tumour is responsible directly or indirectly for most cancer-related deaths.
Clinical management of cancer can be aided by prognosis markers and by therapeutic predictive markers. Prognosis markers assess risk of the disease progression independent of therapy. Therapeutic predictive markers indicate sensibility or resistance of a cancer to a specific treatment. For most cancers and cancer treatments, there exist subsets of patients that will respond to a particular treatment and subsets of patients that will fail to respond to the treatment.
The use of therapeutic predictive markers to identify subsets of patients likely to respond to treatment would facilitate the selection of the appropriate treatment and avoid unnecessary delays associated with ineffective treatment. Additionally, because most cancer treatments are associated with adverse side effects inherent to the treatment, said predictive markers eliminate unnecessary risks of adverse side effects by reducing the administration of cancer treatments to individuals for whom treatment is likely to fail.
Currently, the only recommended therapeutic predictive markers in oncology are ER (estrogen receptor) and PR (progesterone receptor) status for selecting hormone sensitive breast cancers, and HERB-2 for identifying breast cancer patients who may benefit from trastuzumab treatment.
The incidence of brain metastasis in patients with breast cancer overexpressing HERB-2 treated with tratuzumab is twice that in other breast cancer patients. On the other hand, one-third of the patients with breast cancer will develop CNS metastasis and this often occurs when they are responding to therapy at other sites or have a stable disease. Thus, drugs with a high impact on the clinical outcome of metastatic breast cancer patients, such as taxanes or trastuzumab, play only a limited role in the treatment of brain metastasis (Tosoni A. et al., “Chemotherapy in breast cancer patients with brain metastases: Have new chemotherapic agents changed the clinical outcome?”, Crit. Rev. Oncol. Hematol. 2008, vol. 68(3), p. 212-221). The resistance to HERB2-target agents remains a substantial clinical problem as many HERB2-positive cancers exhibit intrinsic resistance.
Cerebral metastases occur in 10-15% of breast cancer patients with advanced disease and have recently become a significant clinical problem. It can be assumed that up to 30% of metastatic breast cancer patients will experience brain metastasis during the course of their disease. The increase in this rate could be linked to greater survival in patients receiving chemotherapy and the fact that it is difficult to overcome the blood brain barrier (BBB) with current systemic treatments. The difficulties in managing brain metastasis therapy result in a median survival of seven months, with brain metastasis being the cause of death or a major contributing factor of it in 68% of patients.
An adequate estimation of independent predictive factors at initial tumor diagnosis is required to enable the clinician to determine whether said tumor can metastasize. This information would be useful for the clinician in order to decide between aggressive treatments, to avoid unnecessary treatment, and to design therapies specifically addressed against differential aspects of each metastatic location.
Therefore, there is the need of predictive markers which provides information about the risk of metastasizing a primary tumor to other organs in order to treat efficiently the illness.